Genetic Influence on Beta-Blocker Therapy

Beta-blockers have grown in influence since their properties were first discovered in 1958. They stand as staples in modern cardiovascular disease management. However, research into their receptor pathway has shown certain genetic factors can have a tremendous influence on beta-blocker pharmacodynamics. Mutations within the targeted receptors and associated regulatory proteins can change typical responses to beta-blocker therapy. Ultimately, a simple genetic test could reveal the difference between a 2-fold response and management altering resistance.

Beta-blockers earned their name because they antagonise the activation of beta-adrenergic receptors. Beta-adrenergic receptors of the β1, β2, and β3 varieties are found throughout the body. The main target is the blockade of β1-receptors found primarily in the heart, creating a negative chronotropic and inotropic effect. Specific beta-blockers are selected based on their selectivity for receptors, the relative degree of antagonism, and duration of action. However, polymorphisms within the receptor protein can also change the effect of beta-blockade and may need to be taken into account when selecting the appropriate therapy.

β1-adrenergic receptors are G protein-coupled receptors encoded by the ADRB1 gene. A single nucleotide polymorphism, called rs1801253, on the beta-blocker binding site can result in a receptor that binds more strongly with the drug. This complex responds more strongly than normal to blockade and is a more easily inactivated receptor, increasing drug efficacy. Homozygous carriers of this ADRB1 variant can have as much as a 2-fold increase in responsiveness to beta-blockers. This can be measured as a drop in blood pressure and increased left ventricular ejection fraction.

Beta-adrenergic receptor activity is managed by a group of G protein receptor kinases encoded by the GRK5 gene. A single nucleotide change in the GRK5 gene results in a protein that is much better at deactivating the beta receptor. Homozygous carriers of this variant have two copies of this hyperactive beta-receptor deactivator. The cumulative effect is an enhanced blood-pressure-lowering response to beta-blocker therapy. However, patients lacking this variant have receptors that may stay active for longer, and may respond poorly to beta-blocker treatment. This effect is pronounced enough that it has been suggested this subgroup of patients could be prescribed ivabradine instead. Ivabradine inhibits the funny current, bypassing beta receptors that may be resistant to traditional therapy.

Clearly, genetics can play a major role in the choice of beta-blocker therapy. Some studies have even shown a possible role for beta-receptor polymorphisms in the development of heart failure. All this data is part of a growing body of evidence that genetic testing for polymorphisms has an important role to play in the management of heart failure and cardiovascular disease. The next step is getting this information into the hands of physicians before the complications it could have prevented occur.

Important: never stop, start or change the dose of a beta-blocker on the basis of a genetic result alone. Stopping a beta-blocker abruptly can cause a dangerous rebound in heart rate and blood pressure. Any change must be made by the clinician who prescribes it.

Pharmacogenetic testing with Rightangled

Rightangled's DNA tests look at genetic markers relevant to cardiovascular health and drug response. Results are reviewed by our clinical team, which includes GPhC-registered independent prescribers, with medical oversight from our doctor, Dr Abdullah, so you receive a clear explanation of what your result means — and what to discuss with your own prescriber.

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Related reading: heart medications: one size does not fit all.

This article is for general information and does not replace personalised medical advice. Never change prescribed medication without speaking to your clinician.